CN117242083A - Composition for chemical synthesis of peptides - Google Patents
Composition for chemical synthesis of peptides Download PDFInfo
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- CN117242083A CN117242083A CN202280030201.9A CN202280030201A CN117242083A CN 117242083 A CN117242083 A CN 117242083A CN 202280030201 A CN202280030201 A CN 202280030201A CN 117242083 A CN117242083 A CN 117242083A
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 88
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 22
- 238000003786 synthesis reaction Methods 0.000 title abstract description 21
- 150000001413 amino acids Chemical class 0.000 claims abstract description 219
- 238000000034 method Methods 0.000 claims abstract description 50
- 238000010647 peptide synthesis reaction Methods 0.000 claims abstract description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 62
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 59
- 229910052760 oxygen Inorganic materials 0.000 claims description 54
- 229910052717 sulfur Inorganic materials 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 41
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 41
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 40
- 238000005859 coupling reaction Methods 0.000 claims description 36
- 230000008878 coupling Effects 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 28
- 238000010168 coupling process Methods 0.000 claims description 26
- -1 methoxyphenyl Chemical group 0.000 claims description 24
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 18
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 18
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000000134 2-(methylsulfanyl)ethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])[*] 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 description 97
- 125000005647 linker group Chemical group 0.000 description 43
- 239000012071 phase Substances 0.000 description 15
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 238000004873 anchoring Methods 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 101800004807 Gonadotropin-releasing hormone-associated peptide Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 101150110932 US19 gene Proteins 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical group [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000011191 terminal modification Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 1
- KXMUQDJHHXLOLC-UHFFFAOYSA-N 1-(9h-fluoren-1-ylmethyl)piperidine Chemical compound C=1C=CC(C2=CC=CC=C2C2)=C2C=1CN1CCCCC1 KXMUQDJHHXLOLC-UHFFFAOYSA-N 0.000 description 1
- UPMGJEMWPQOACJ-UHFFFAOYSA-N 2-[4-[(2,4-dimethoxyphenyl)-(9h-fluoren-9-ylmethoxycarbonylamino)methyl]phenoxy]acetic acid Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(O)=O)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPMGJEMWPQOACJ-UHFFFAOYSA-N 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 101150013568 US16 gene Proteins 0.000 description 1
- 101150049278 US20 gene Proteins 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- NXGAOFONOFYCNG-UHFFFAOYSA-N diphenylphosphorylmethylbenzene Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)CC1=CC=CC=C1 NXGAOFONOFYCNG-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001846 repelling effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3229—Esters of aromatic acids (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/36—Amides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
Abstract
The present disclosure relates to compositions that can act as anchors for chemical synthesis of peptides. The anchor molecule may include GAP components, linker components, amino acid components, and/or terminator components. The anchor molecule may also include an anchor peptide, wherein the anchor peptide may be removably coupled to an amino acid of a given sequence and act as a GAP anchor by enabling solubility control of the target peptide when the target peptide is synthesized via the addition of one or more other amino acids; the anchor peptide may then be removed from the target peptide. Also provided are novel methods of peptide synthesis utilizing the novel anchors and/or anchor peptides.
Description
Cross Reference to Related Applications
The present application claims priority from U.S. provisional patent application Ser. No. 63/201,313, entitled "Compositions for Chemical Synthesis of Peptides [ composition for chemical Synthesis of peptides ]", filed on 4/23 of 2021. The application cross-references: i) PCT application No. PCT/US16/68112, "System and method for solution phase GAP peptide synthesis [ systems and methods for solution phase GAP peptide synthesis ]", filed on 2016, 12, 21; ii) PCT application No. PCT/US19/29569, "Method for Solution-Phase Peptide Synthesis [ methods for solution phase peptide synthesis ]", filed on 29 th 4 th 2019; iii) PCT application No. PCT/US19/33296, "Method for Solution-Phase Peptide Synthesis and Protecting Strategies Thereof [ methods for solution phase peptide synthesis and protection strategies therefor ]", filed on 2019, 5, 21; iv) PCT application No. PCT/US20/15132, filed on 26 th month 1 in 2020; v) U.S. application Ser. No. 17/104,166, filed 11/25/2020 and published as U.S. 2021/0079036 A1 entitled "Compositions and Methods for Chemical Synthesis [ compositions and methods for chemical Synthesis ]"; and vi) U.S. provisional patent application Ser. No. 63/201,313, entitled "Compositions for Chemical Synthesis of Peptides [ composition for chemical Synthesis of peptides ]", filed on month 4 and 23 of 2021; and these applications are incorporated herein by reference as examples.
Statement of federally sponsored research or development
And no.
References to sequence Listing, tables, or computer Listing CD appendices
And no.
Background
Recent research efforts have made significant progress in the field of purification chemistry, particularly focused on avoiding column chromatography and recrystallization. This study has been defined as a group-assisted purification (GAP) chemistry/technique as a chemical method of organic synthesis that avoids traditional purification methods such as chromatography and/or recrystallization by purposefully introducing well-functionalized groups in the starting materials or the newly generated products. These GAP groups may also be generally used as protecting groups to prevent undesired side reactions during synthesis of the target molecule. Such studies have the potential to cover the whole field of synthetic organic chemistry.
Protecting groups are found in almost every complex synthesis where multiple functional groups are present. Effective protecting groups need to be robust to a variety of conditions and must be added and removed in high yields. Protecting groups are widely used in peptide synthesis, whether for solid phase or solution phase methods. One of the most commonly used protecting group strategies for peptide synthesis is Fmoc/tBu. Fmoc/tBu chemistry is extremely attractive for peptide synthesis for several reasons, such as availability of starting materials, production costs, and relatively mild conditions required for deprotection. U.S. patent No. 8,383,770B2 teaches the use of fluorenylmethoxycarbonyl (Fmoc) and t-butoxycarbonyl (Boc) N-terminal protecting groups in Solid Phase Peptide Synthesis (SPPS), and this technique is well known and widely used in the industry.
SPPS developed by Merrifield in the 60 s of the 20 th century has become the standard solution used by a number of scientific disciplines for research and manufacture. The main disadvantage of SPPS is that it is difficult to scale up: many polymeric carriers are expensive and occupy a substantial portion of the mass of the material to be treated. The coupling reaction in SPPS is also inefficient because the reaction occurs at the solid-liquid interface. In addition, after each deprotection and coupling reaction, the resin must be washed with a solvent to remove any impurities resulting from the previous reaction, and this creates a large amount of solvent waste, which can be a significant problem in large scale cases.
However, despite these disadvantages of SPPS and the attractive force of Fmoc/tBu chemistry, few examples of economically viable Fmoc protection schemes for solution phase peptide synthesis (SolPPS) exist. U.S. patent No. 5,516,891A provides one of a few examples of Fmoc-based SolPPS. Also, fmoc peptide synthesis is almost entirely limited to SPPS due to the formation of N-fluorenylmethylpiperidine (NFMP) as a byproduct during deprotection, which is difficult to remove without a polymeric carrier. The standard protocol for Fmoc deprotection is to stir the Fmoc-peptide in a solution of Dimethylformamide (DMF) or Dichloromethane (DCM) with excess piperidine, deprotect the Fmoc group in the process and form NFMP. The' 891 patent teaches removal of this impurity by deprotection with 4-aminomethylpiperidine (4 AMP) instead of piperidine. This forms NFMP-CH 2 NH 2 Rather than NFMP, it can be extracted into water due to the presence of additional amino groups. The 4AMP also eliminates the active amino acid ester and is capable of removing the 4 AMP-amino acid product from the reaction mixture via washing. A significant problem with this approach is the use ofThe high cost of 4AMP makes this approach too costly and prevents it from being widely accepted in the industry.
Another example of Fmoc-based SolPPS can be found in published patent application WO2017112809 A1. This publication teaches the use of C-terminal GAP protecting groups, benzyldiphenylphosphine oxide (HOBnDpp), to control the solubility of the target peptide to allow selective precipitation after each successive coupling reaction. Controlling the solubility such that the growing peptide is maintained in an organic solvent such as ethyl acetate or DCM, and performing water washing to remove impurities; the organic solvent is then concentrated, and the mixture in the alkane solvent is then concentrated to selectively precipitate the peptide product. While this technique converts Fmoc/tBu chemistry to solution phase in a much more economically viable manner than the' 891 patent, this approach also presents potential limitations, such as challenges in removing GAP protecting groups from peptides; maintaining solubility control for longer sequences; unexpected cleavage of GAP protecting groups during coupling/deprotection reactions; c-terminal modification cannot be easily performed; and racemization, such as at the coupling point between the GAP protecting group and the peptide.
Summary of The Invention
The present application provides several advantages in the art. In one embodiment, a novel solution phase peptide synthesis method is presented that utilizes a modular approach to anchoring that can increase solubility control for a given peptide sequence. In another embodiment, the application includes the use of a peptide as an anchor to synthesize a peptide of interest. Preferably, in one embodiment, the peptide may include a functionalized protecting group that may aid solubility.
In one embodiment, the present application may include a chemical composition comprising a GAP component, a terminating group component, and a linker component. In another embodiment, the application may include a method of solution phase peptide synthesis, and the method may include the steps of: attaching a first peptide to a first amino acid; coupling one or more additional amino acids to the first amino acid to form a second peptide; and removing the first peptide from the second peptide.
In another embodiment, the application may include a method of forming an anchor peptide for solution phase peptide synthesis, and the method may include the steps of: coupling the first protected amino acid to the second protected amino acid; and attaching a linker to the first or second protected amino acid.
In another embodiment, the application may include a chemical composition, which may be selected from the group consisting of:
in another embodiment, the application may include a method of peptide synthesis, and the method may include attaching a first protecting group to a first side chain of a first amino acid; coupling a second protecting group to a second side chain of a second amino acid; coupling a first amino acid with a second amino acid; attaching a linker to the end of the first or second amino acid; attaching a linker to the third amino acid; and coupling the fourth amino acid to the third amino acid.
In another embodiment, the present application may include a chemical composition comprising a GAP component selected from the group consisting of:
wherein: r is R 4 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 5 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 6 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30; r is R 7 Selected from the group consisting ofThe group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30; r is R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30; r is R 9 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p4 -wherein "p4" is an integer selected from the range of 0 up to 30 and including 30; r is R 10 Selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30; "j" is an integer selected from the range of 0 up to 30 and including 30; and "k" is an integer selected from the range of 0 up to 30 and including 30. Further comprising a linker component, wherein the linker component is selected from the group consisting of:
wherein Y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O; v is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a1 -wherein "a1" is an integer selected from the range of 0 up to 30 and including 30; w is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a2 -, wherein "a2" is an integer selected from the range of 0 up to 30 and including 30; x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30; r is R 1 Selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30; r is R 2 Selected from the group consisting ofThe group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and "n" is an integer selected from the range of 0 up to 30 and including 30. Further comprising a terminating group component, wherein the terminating group component is selected from the group consisting of:
wherein R is 4 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 5 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 6 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q1 -wherein "q1" is an integer selected from the range of 0 up to 30 and including 30; r is R 7 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q2 -wherein "q2" is an integer selected from the range of 0 up to 30 and including 30; r is R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q3 -wherein "q3" is an integer selected from the range of 0 up to 30 and including 30; r is R 9 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q4 -wherein "q4" is an integer selected from the range of 0 up to 30 and including 30; r is R 11 Selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh; r is R 12 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30; r is R 13 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (C)H 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and R is 14 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30. Further comprising a linker component, a terminator component, and a first amino acid component, wherein the GAP component is
Wherein R is 4 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 5 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 6 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p1 -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30; r is R 7 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30; r is R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30; r is R 9 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p4 -wherein "p4" is an integer selected from the range of 0 up to 30 and including 30; r is R 10 Selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30; "j" is an integer selected from the range of 0 up to 30 and including 30; and "k" is an integer selected from the range of 0 up to 30 and including 30; the linker component being
Wherein: y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O; w is-C (O) -; x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30; r is R 1 Selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30; r is R 2 Selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and "n" is an integer selected from the range of 0 up to 30 and including 30; the first amino acid component being
Wherein Z is 1 Selected from the group consisting of: s, O, NH, NMe, net, NBn, NPh, -C (O) -and- (CH) 2 ) d -, wherein "d" is an integer selected from the range of 0 up to 30 and including 30; z is Z 2 Selected from the group consisting of: s, O, NH, NMe, net, NBn, NPh, -C (O) -and- (CH) 2 ) e -wherein "e" is an integer selected from the range of 0 up to 30 and including 30; "f" is an integer selected from the range of 0 up to 30 and including 30; "g" is an integer selected from the range of 0 up to 30 and including 30; r is R 3 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl, 2- (methylsulfanyl) ethyl, Wherein "h" is an integer selected from the range of 0 up to 30 and including 30; and
the terminating group component being
Wherein R is 11 Selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh; r is R 12 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30; r is R 13 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and R is 14 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30. Comprising:
in another embodiment, the application may include a chemical composition comprising a GAP component, a terminator component, and a linker component, wherein the GAP component is
Wherein: r is R 6 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p1 -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30; r is R 7 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30; r is R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30; r is R 10 Selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30; "j" is an integer selected from the range of 0 up to 30 and including 30; and "k" is an integer selected from the range of 0 up to 30 and including 30; the linker component being
Wherein Y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O; w is-C (O) -; x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30; r is R 1 Selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30; r is R 2 Selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and "n" is an integer selected from the range of 0 up to 30 and including 30; and the terminating group component is
Wherein R is 11 Selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh; r is R 12 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30; r is R 13 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and R is 14 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30. Comprising:
in another embodiment, the application may include a chemical composition comprising a GAP component, a terminator component, and a linker component, wherein the GAP component is
The linker component being
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Wherein Y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O; v is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a1 -, wherein "a1" is selected from the range of 0 up to 30 andand includes an integer of 30; w is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a2 -, wherein "a2" is an integer selected from the range of 0 up to 30 and including 30; x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30; r is R 1 Selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30; r is R 2 Selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and "n" is an integer selected from the range of 0 up to 30 and including 30; and the terminating group component is
Wherein R is 4 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 5 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl; r is R 6 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q1 -wherein "q1" is an integer selected from the range of 0 up to 30 and including 30; r is R 7 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q2 -wherein "q2" is an integer selected from the range of 0 up to 30 and including 30; r is R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q3 -wherein "q3" is an integer selected from the range of 0 up to 30 and including 30; and R is 9 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q4 -wherein "q4" is an integer selected from the range of 0 up to 30 and including 30. Comprises
In another embodiment, the application may include a method of solution phase peptide synthesis comprising the steps of: attaching a first peptide to the first amino acid, wherein the first peptide is an anchor peptide; coupling one or more additional amino acids to the first amino acid to form a second peptide; and removing the first peptide from the second peptide. Wherein the first peptide comprises a GAP component. Wherein the first peptide is formed by coupling a first protected amino acid to a second protected amino acid and attaching a linker to the first or second protected amino acid, wherein the first protected amino acid is formed by attaching a first protecting group to a first side chain of the first amino acid component and the second protected amino acid is formed by coupling a second protecting group to a second side chain of the second amino acid component. Further comprising the steps of: coupling the first amino acid component with the second amino acid component; attaching a linker to the terminus of the first or second amino acid component; attaching a linker to the third amino acid; and coupling the fourth amino acid to the third amino acid.
In another embodiment, the application may include a method of peptide synthesis comprising the steps of: coupling an anchor to the first amino acid, and coupling a second amino acid to the first amino acid, wherein the anchor comprises a compound selected from the group consisting of:
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wherein the anchor is coupled to the C-terminus of the first amino acid. Wherein the anchor is coupled to a side chain of the first amino acid. Wherein the compound is
And wherein the anchor is coupled to the C-terminus of the first amino acid via the linker component. Wherein the anchor further comprises a terminating group component. Further comprising the step of removing the anchor from the first amino acid. Wherein the coupling of the second amino acid to the first amino acid occurs in 2-methyltetrahydrofuran.
Brief Description of Drawings
The foregoing and other objects, features and advantages of the application will be apparent from the following description of embodiments as illustrated in the accompanying drawings in which reference characters refer to the same parts throughout the various views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the application. These figures are used as non-limiting examples and are intended only to depict preferred embodiments and not to limit the scope of the application:
FIG. 1A illustrates exemplary GAP components in accordance with the principles of the present application;
FIG. 1B illustrates an exemplary AA (Gap) composition in accordance with the principles of the present application;
FIG. 2 illustrates exemplary amino acid components in accordance with the principles of the present application;
FIG. 3 illustrates exemplary linker components according to principles of the application;
FIG. 4 illustrates an exemplary termination base component according to the principles of the present application;
FIG. 5 illustrates exemplary anchor molecules and/or anchor peptides having exemplary infrastructure schematics according to the principles of the present application;
FIG. 6 illustrates an exemplary anchor molecule having an exemplary infrastructure schematic according to the principles of the present application;
FIG. 7 illustrates exemplary anchor molecules and/or anchor peptides having exemplary infrastructure schematics according to the principles of the present application; and
fig. 8 illustrates an exemplary modular anchoring method according to principles of the present application.
Detailed Description
In the foregoing summary and detailed description, reference is made to specific features of the application in the following claims and drawings. It should be understood that the disclosure of the present application in this specification includes all possible combinations of such specific features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the application, or of a particular claim, that feature may also be used in combination with and/or in the context of other particular aspects and embodiments of the application, to the extent possible, and generally in the application.
In accordance with the present application, all of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation. While the compositions and methods of this application have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the application. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the application as defined by the appended claims.
The term "comprise" and grammatical equivalents thereof are used herein to mean that other components, ingredients, steps, etc., are optionally present. For example, an article that "comprises" (or "comprises/includes") components A, B and C may consist of (i.e., contain only) components A, B and C, or may contain not only components A, B and C, but also one or more other components.
Where a method comprising two or more defined steps is referred to herein, the defined steps may be performed in any order or concurrently (except where the context excludes the possibility), and the method may comprise one or more other steps performed before any defined step, between two of the defined steps, or after all defined steps (except where the context excludes the possibility).
The term "at least" followed by a number is used herein to denote the beginning of the range starting with that number (which may be a range with or without an upper limit, depending on the variable defined). For example, "at least 1" means 1 or more than 1. The term "up to" digit(s) is/are used herein to denote the end of a range ending in that digit (which may be a range having 1 or 0 as its lower limit, or a range without a lower limit, depending on the variables defined). For example, "up to 4" means 4 or less than 4, and "up to 40%" means 40% or less than 40%. In this specification, when a range is given as "(initial number) to (subsequent number)" or "(initial number) - (subsequent number)", this means a range whose lower limit is the initial number and whose upper limit is the subsequent number. For example, 25 to 100mm means a range whose lower limit is 25mm and whose upper limit is 100 mm.
"amino acid" is a term commonly understood in the art. In the broadest sense, an amino acid may be any organic molecule containing both amino and carboxylic acid groups. For practical applications, the size of these molecules may generally be less than 1,000 daltons, with the amino group (N-terminal) and carboxylic acid group (C-terminal) separated by only one or two methylene units. An additional feature of amino acids may be the presence of side chains as branches from the separation of the N and C terminal methylene units. The side chains may include virtually any structural feature, and changes in the side chains account for changes in the amino acids. Such variations include, but are not limited to, the standard twenty protein amino acids, as well as other amino acids such as ornithine or selenocysteine. Many non-protein structures may also be considered amino acids, such as phenylglycine, and thus the term is not limited to a subset of twenty. "protected" amino acids may be considered a subclass of amino acids in which certain functional groups, such as, by way of non-limiting example, the N-terminus and/or portions of a side chain, are attached to a protecting group to temporarily inhibit the reactivity of the protected functional group. In the context of the present application, a "GAP amino acid" may be an amino acid in which the side chain and/or the C-terminal and/or N-terminal contain and/or are attached to one or more GAP groups. As used herein, a "GAP group" may include a GAP component (GAP anchor) (GAP protecting group), as discussed further below. GAP groups may include, but are not limited to, phosphine oxide moieties.
As mentioned above, the amino acid "side chain" may be a branch from the separation of the N and C terminal methylene units, and may sometimes also be commonly referred to as an "R" group. The side chains may include virtually any structural feature, and changes in the side chains account for changes in the amino acids.
"peptide" is a term commonly understood in the art as a biopolymer made from amino acid monomers. At least two amino acids must be bonded together to form a peptide. As used herein, "anchor peptide" may include peptides that also act as an anchor-for anchor peptides, peptides are prepared that may then act as anchors to synthesize a second target peptide. For the purposes of the present application, anchor peptides may include peptides having 20 amino acids or less. An "anchor" as used herein may be a molecular group attached or designed for attachment to a target molecule (such as a peptide) with the purpose of controlling the solubility characteristics of the peptide during its synthesis in order to facilitate the synthesis of the peptide in a practical manner. The anchors may typically be removed at the end of peptide synthesis and may not be a component of the final target molecule. However, upon removal of the anchor, in some embodiments, the molecular components of the anchor may remain, such as to effect, for example, C-terminal modification (such as may be achieved via a known Rink Amide linker). As used herein, "GAP anchors" may include anchor molecules comprising GAP groups. The anchors may include GAP components (discussed below). In one embodiment, the GAP component itself may act as an anchor.
In one embodiment, the present application may include the structure of an anchor molecule for group-assisted purification of peptide synthesis (GAP-PS). In one embodiment, the anchor molecule may be coupled to the first amino acid in the peptide sequence without causing significant racemization. In another embodiment, the anchor molecule may be conditionally stable to the amino acid coupling and Fmoc deprotection steps. In another embodiment, the anchor molecule may be cleaved from the peptide either simultaneously with the side chain protecting group or via an orthogonal method without causing racemization. In another embodiment, the anchor may provide significant control over solubility. For example, in one embodiment, the anchor molecule may completely exclude the protected peptide from dissolving in water or a water/organic solvent mixture wherein the water content is > 50%. In one embodiment, failure of the anchor to do this may result in low yields due to repeated loss of product during aqueous work-up. In another embodiment, the anchor may also promote solubility of the protected peptide in the selected organic solvent such that the peptide may be completely dissolved to form a homogeneous solution of a concentration suitable for large scale manufacturing, typically on the order of 10-20mL solvent/gram solute. In another embodiment, the anchor may be a protecting group capable of "anchoring" the target molecule in a particular solvent.
In another embodiment, the application may include anchors that provide significant improvements to these aforementioned characteristics as well as additional benefits. For example, anchors contemplated herein may include GAP protected amino acids, and in another example, such GAP protected amino acids are utilized to modularly construct anchors that can be tailored to the peptide being synthesized. In another embodiment, the present application may include a system that can construct anchors (GAP anchors) using rapid and reliable chemical reactions of peptide coupling and deprotection reactions. In some embodiments, the GAP anchors may include anchor peptides (GAP anchor peptides). In one embodiment, the anchor peptide may be an anchor having a peptide bond; in another embodiment, the anchor peptide may be any peptide; in another embodiment, the anchor peptide may be any molecule having a peptide bond that is soluble in a polar organic solvent and insoluble in water. In another embodiment, the anchor peptide may be any molecule having a peptide bond that may be removably attached to the target molecule to facilitate solubility control and subsequently removed from the target molecule. In another embodiment, anchors comprising one, two, three, or more GAP amino acids may be synthesized quickly for varying degrees of control over solubility, e.g., may be balanced against cost. For example, synthesis of 30-mer peptides can be achieved via the use of three GAP amino acids in the anchor to adequately control the solubility of the peptide of that size; however, in another example, the 5-mer peptide may be implemented using an anchor with one of the GAP amino acids. In another example, the same GAP amino acid may be synthesized as a co-starting material for both anchors and may be rapidly assembled into anchors in a manner consistent with the needs of the target molecule and in a manner that balances the required control with the anchor synthesis and atomic economic costs.
In one embodiment, and due to the increased stability, additional process advantages may be realized. In another embodiment, the increased stability of the GAP amino acid anchors may allow the coupling and deprotection reactions to be performed in wet organic solvents (water content < 10%). This may, for example, eliminate the need for time consuming and thus expensive drying steps, which may include filtration through solid desiccant and/or azeotropic distillation. In another embodiment, by eliminating the need for these processing steps, the present application provides significant advantages, as the overall synthesis can be significantly faster, meaning that more coupling cycles can be achieved in a shorter period of time. Such advantages may have a significant positive effect on the cost of the peptide synthesis, especially for longer peptides requiring more coupling cycles.
In one embodiment, the application may include utilizing amino acids and/or peptides in combination with protecting groups to form an anchor molecule for solution phase peptide synthesis. For example, amino acids may be protected at their side chains and/or ends by protecting groups (e.g., GAP protecting groups) and further coupled to each other (and/or to other molecules) to form an anchor molecule.
In one embodiment, the present application may include chemical compositions that may include one or more group-assisted purification (GAP) components (in one embodiment, each GAP component may preferably be less than 300 daltons); one or more Amino Acid (AA) components; one or more linker components; and/or one or more terminating group (cap) components. In another embodiment, the GAP component may be an amino acid-GAP component (AA (GAP) component). In one embodiment, the GAP component and the linker groupThe components may be GAP components and linker components (respectively) as described in U.S. application Ser. No. 17/104,166. In another embodiment, the terminating group component may be similar or identical to the spacer component discussed in U.S. application Ser. No. 17/104,166. In one embodiment, the application may include H-AA (Gap) -OH, H- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -terminator, H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ A terminator group, and/or an H-linker- { [ AA1] α -[AA(Gap)] β -[AA2] γ -termination base } δ Structures of the type, which may be collectively referred to as H-anchor (GAP anchor) molecules, where H may refer to elemental hydrogen; o may refer to elemental oxygen; alpha, beta and gamma may be any integer from 0 up to 10 and including 10; delta may be any integer from 0 up to 2 and including 2; AA (Gap) may be an amino acid-Gap component (e.g., an amino acid attached to the Gap component); the linker may be a linker component similar to those discussed herein and known in the art; AA (AA) 1 And/or AA 2 May be any type of amino acid or amino acid moiety; and the terminating group may be, for example, any chemical moiety that is largely chemically inert, has very low solubility in water, does not interfere with the solubility of the anchor molecule in organic solvents, and contains a nucleophilic moiety at one end so that other chemical moieties and/or components of the anchor molecule may be attached using standard peptide coupling reagents.
Any variables used herein that may have similar values need not be the same value. For example, and in one embodiment, R 4 And R is 5 Both may be any of H, methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, or tert-butyl-which may be the same or different. In addition, in the case of the optical fiber,the attachment point of a given molecule to any other molecule can be depicted.
For example, and in another embodiment illustrated in fig. 1A, the GAP component may include:
(HNtBuODpp) in whichThe attachment of the GAP component to another molecule or atom, such as to an amino acid (e.g., with respect to the AA (GAP) component), may be depicted. For example, and in one embodiment, HNtBuODpp (or another GAP component) may be coupled to an amino acid side chain or C-terminal to form an AA (GAP) component. In one embodiment, attaching the GAP component to the amino acid side chain or C-terminus may allow the C-terminus or side chain (respectively) of the amino acid to freely participate in coupling reactions, such as coupling reactions with additional GAP protected amino acids. Preferably, one or more AA (Gap) components may be contained in the anchor molecule, or the anchor molecule. In another embodiment, two or more AA (Gap) components may be coupled together, such as to form an anchor or a portion of an anchor. In one example, by utilizing two or more AA (Gap) components, peptide-based anchors can be formed to achieve solution phase peptide synthesis.
In another embodiment, the GAP component may be an AA (GAP) component and may preferably include amino acids coupled to a group-assisted purification molecule. For example, the AA (Gap) component may include a Gap component and an amino acid component. In another embodiment, the AA (Gap) component (e.g.,) May include the following structures (such as those related to anchors, including H-AA (Gap) -OH, H- [ AA) as illustrated in FIG. 1B 1 ] α -[AA(Gap)] β -[AA 2 ] γ -terminator, H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group), and/or an H-linker- { [ AA1] α -[AA(Gap)] β -[AA2] γ -termination base } δ ：
Wherein R is 10 Can be-C (O) -, - (CH) 2 ) m -, or NH; r is R 6 、R 7 、R 8 And R is 9 Can be-C (O) -, S, O, NH, NMe, net, NBn, NPh, or- (CH) 2 ) p -any one of the following; r is R 4 And R is 5 May be H, methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, or tert-butyl; and j, k, m and p may each be a separate value, which may be any integer from 0 up to 30 and including 30. R is R 6 、R 7 、R 8 And R is 9 May all be different and for R 6 、R 7 、R 8 And R is 9 And each "p" of (c) may be a different value.
In another embodiment, the anchor may comprise an amino acid component (AA component), such as in addition to the GAP component or the AA (GAP) component, such as in relation to anchors, including H-AA (GAP) -OH, H- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group, and/or an H-linker- [ AA ] 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group. In one embodiment, the amino acid component may be any molecule having a primary or secondary amine and a carboxylic acid. In another embodiment, and as shown in fig. 2, the amino acid component (e.g.) May include:
wherein Z is 1 Can be S, O, NH, NMe, net, NBn, NPh, -C (O) -, or- (CH) 2 ) d -；Z 2 Can be S, O, NH, NMe, net, NBn, NPhC (O) -, or- (CH) 2 ) e -; d. e, f, g, h each may be a value that may be any integer from 0 up to 30 and including 30; and R is 3 May be H, methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl, 2- (methylsulfanyl) ethyl, or:
in another embodiment, the anchor may include a linker component (linker), such as in addition to the GAP component and/or the AA (GAP) component, such as with respect to the anchor, including H-AA (GAP) -OH, H- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -terminator, H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ A terminator group, and/or an H-linker- { [ AA1] α -[AA(Gap)] β -[AA2] γ -termination base } δ . In one embodiment, the linker component may include linkers known in the art for peptide synthesis. In another embodiment, and as shown in fig. 3, the linker component (e.g. ) May include: />
Wherein Y may be S, NH, NMe, NEt, NBn, NPh, or O; v may be S, NH, NMe, NEt, NBn, NPh, O, -C (O) -, - (CH) 2 ) a1 -; w can be S, NH, NMe, NEt, NBn, NPh, O, -C (O) -, - (CH) 2 ) a2 -; x may be S, NH, NMe, NEt, NBn, NPh, O, -C (O) -, - (CH) 2 ) a3 -；R 1 May be- (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, or diA methoxyphenyl group; r is R 2 May be- (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, or dimethoxyphenyl; and a, b, c and n may be individual values that may be any integer from 0 up to 30 and including 30. In one embodiment, "H" (hydrogen) in "H-linker" (in, for example, H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ Termination and/or H-linker- { [ AA1] α -[AA(Gap)] β -[AA2] γ -termination base } δ As used herein) is attached to the "Y" variable of the linker (such attachment marked above with wavy lines).
In another embodiment, the anchor may include a terminating group component (terminating group), such as in addition to the GAP component and/or the AA (GAP) component and/or the linker component, such as in relation to the anchor, including H-AA (GAP) -OH, H- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -terminator, H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ A terminator group, and/or an H-linker- { [ AA1] α -[AA(Gap)] β -[AA2] γ -termination base } δ . In one embodiment, and as shown in fig. 4, a terminating base component (e.g.) May include:
wherein R is 11 May be S, O, NH, NMe, net, NBn, or NPh; r is R 12 、R 13 And R is 14 Can be H, methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q -any one of H; r is R 6 、R 7 、R 8 And R is 9 Can be-C (O) -, S, O, NH, NMe, net, NBn, NPh, or- (CH 2) q -middle (middle)Any of (2) to (3); r is R 4 And R is 5 May be any of H, methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, or tert-butyl; and q may be any integer from 0 up to 30 and including 30. R is R 4 、R 5 、R 6 、R 7 、R 8 And R is 9 May all be different from each other, and the q values of the different R groups may be different.
In another embodiment, the application may include compositions, such as compositions that may be used as anchors in accordance with the principles of the application. For example, and as shown in fig. 5, the anchor may include:
in this example, the anchor may follow the H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group form, wherein α may be 0, β may be 2, and γ may be 1. In one embodiment, each component may be defined as follows:
For the linker: wherein y=o; r is R 1 ＝H；R 2 =h; x=o and has a Me group at the para position and other X-containing groups at the ortho position; n=1
For AA (Gap): r is R 4 And R is 5 Methyl group: r is R 7 ＝O；R 6 And R is 8 ＝-(CH 2 ) p Wherein p=0; r is R 9 ＝NH；R 10 ＝-C(O)-；j＝0；k＝1
For AA 2 ：Z 1 ＝NH；f＝0；R 3 ＝H；g＝0；Z 2 ＝-C(O)-
For the terminating group: r is R 11 ＝NH：R 12 ＝-(CH 2 ) q -H, wherein q = 15; r is R 13 And R is 14 ＝H
In another embodiment, and as shown in fig. 6, the anchor molecule may comprise:
in this example, the anchor may follow the H-linker- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group form, wherein α may be 0, β may be 1, and γ may be 0. In one embodiment, each component may be defined as follows:
for the linker: wherein y=nh; r is R 1 ＝H；R 2 Dimethoxyphenyl group with methoxy groups at positions 2 and 4; x=o and at the para position; n=1
For AA (Gap): r is R 6 And R is 8 ＝-(CH 2 ) p -wherein p = 0; r is R 7 ＝NH；R 10 ＝-(CH 2 ) m -wherein m = 0; j=4; k=0
For the terminating group: r is R 11 ＝NH；R 12 ＝-(CH 2 ) q -H, wherein q = 15; r is R 13 And R is 14 ＝H
In another embodiment, and as shown in fig. 7, the anchor molecule may comprise:
in this example, the anchor may follow H- [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -a terminating group form, wherein α may be 0, β may be 3, and γ may be 0. In one embodiment, each component may be defined as follows:
for AA (Gap): r is R 4 And R is 5 Methyl group; r is R 7 ＝O；R 6 And R is 8 ＝-(CH 2 ) p Wherein p=0; r is R 9 ＝NH；R 10 ＝-C(O)-；j＝0；k＝1
For the terminating group: r is R 11 ＝NH；R 12 ＝-(CH 2 ) q -H, wherein q = 15; r is R 13 And R is 14 ＝H
In another embodiment, and as shown in fig. 9, the anchor molecule may comprise:
in this example, the anchor may follow the H-linker- { [ AA 1 ] α -[AA(Gap)] β -[AA 2 ] γ -termination base } δ In the form where α may be 0, β may be 0, γ may be 0, and δ may be 2. In one embodiment, each component may be defined as follows:
for the linker: y=nh; v= - (CH) 2 ) a -wherein a = 0; x=o; w= -C (O) -; r is R 1 ＝-(CH 2 ) b -H, wherein b = 0; r is R 2 ＝-(CH 2 ) c -H, wherein c=0; n=10
For the terminating group: r is R 9 ＝NH；R 5 And R is 4 Methyl group; r is R 6 And R is 8 ＝-(CH 2 ) q -wherein q = 0; r is R 7 ＝O
In another embodiment, the application may include a method of synthesizing an anchor (in some embodiments, an anchor peptide). In one embodiment, the method may be a modular system such that the initial starting material (e.g., AA (Gap) component) may be prepared in bulk and then incorporated into the anchor to different extents such that the anchor may have different characteristics depending on the extent of incorporation of the starting material. For example, with respect to the synthesis of the anchors depicted in fig. 7, the AA (Gap) component may be a Gap amino acid (e.g., an amino acid having a protecting group, preferably a Gap protecting group, attached thereto) and may further serve as a modular starting material. For example, and as depicted in fig. 8, the synthesis method may begin with:
In one embodiment, this step may be considered to be an AA (Gap) component and a terminating group component (e.g., H 2 NC 16 H 33 ) Is attached to the base. The product of the above reaction may be:
in one embodiment, the above molecule may then be coupled to the first amino acid of the peptide, or alternatively, the linker component may be further incorporated prior to attachment to the first amino acid. In another embodiment, the application may further comprise adding one or more additional AA (Gap) components to the above molecules. For example, for the synthesis of longer peptide sequences (e.g., 25 amino acids to 100 amino acids), it may be advantageous to include at least one other AA (Gap) component in the anchor, so that as the sequence is extended, the solubility of the peptide of interest can be further controlled. In one example, the above molecules can be reacted with another AA (Gap) component (e.g., the same or different AA (Gap) component as previously used) to achieve:
in one embodiment, the above molecule may then be coupled to the first amino acid of the peptide, or alternatively, the linker component may be further incorporated prior to attachment to the first amino acid. In another embodiment, the application may further comprise adding one or more additional AA (Gap) components to the above molecules. For example, the above molecule may be coupled to another AA (Gap) component to produce:
In one embodiment, the above molecule may then be coupled to the first amino acid of the peptide, or alternatively, the linker component may be further incorporated prior to attachment to the first amino acid. In another embodiment, the application may further comprise adding one or more additional AA (Gap) components to the above molecules.
The method illustrated in fig. 8 may be considered a modular system in which one or more units (e.g., AA (Gap) components) may be added as many times as necessary to achieve greater and greater solubility control. Such modularity is advantageous in the art because it enables large scale synthesis and storage of the starting materials, which can then be converted to custom anchors as desired. Those skilled in the art will appreciate that a variety of different amino acids may be used in this method to provide different characteristics to the anchor. It will be further appreciated that the terminating group component may be modified to provide desired characteristics, such as increased hydrophobicity, increased hydrophilicity, increased aromaticity, and/or any other desired trait. The coupling and deprotection reactions may take place in one or more solvents such as, for example, dichloromethane, DMF, ethyl acetate, tetrahydrofuran, and/or 2-methyltetrahydrofuran.
In one embodiment, GAP, linker, amino acid, and terminator components may be considered as separate chemical entities capable of providing different useful properties to a given GAP anchor. For example, GAP components may include GAP molecules comprising polar bonds (e.g., phosphine oxides) and aromatic components coupled to amino acids, which ultimately impart polar organic properties to anchors with pi-pi stacking potential, which may assist in selective precipitation of the anchors (and attached target molecules) from non-polar solvents; in another embodiment, this may assist the anchor itself in repelling both aqueous and non-polar solvents. In one embodiment, the linker component may provide the anchor with the ability to be selectively removed from the desired substrate while also providing the anchor with the desired solubility characteristics in the same anchor. For example, the linker component may be specifically designed to form a non-labile bond at one position and additionally form a labile bond at another position. This orthogonality can ultimately be translated to an anchor; the GAP component together with the linker component may in this way provide a GAP anchor with polar-organic properties, lending itself to group-assisted purification chemistry, and may otherwise be cleaved under conditions where the linker component itself would otherwise be accommodated. In another embodiment, the terminating group component can provide further desirable characteristics to the anchor in the same (or different) anchor. For example, the terminating group can be highly organic or nonpolar, increasing the overall solubility of the anchor in nonpolar solvents; in another example, the terminating group can be highly polar, such that the anchor can also be more polar and thus poorly soluble in non-polar organic solvents.
In accordance with the principles of the present application, anchors can therefore be specifically tailored to aid in the synthesis of a given molecule with specific characteristics. For example, and as discussed further herein, the desired peptide may be synthesized with the aid of an anchor. The GAP component of the anchor (including the AA (GAP) component) may have the characteristics discussed herein that help render the anchor (and attached peptide) soluble in organic solvents; the GAP component may also be subject to pi-pi stacking to assist in selective precipitation of peptides, such as via droplet precipitation. These features can be further emphasized in anchors by including more than one AA (Gap) component in one anchor molecule. For example, two AA (Gap) components may be coupled together via the ends of amino acids therein, such as via well known coupling reactions, to form a protected peptide. In one embodiment, the GAP protected peptide may be incorporated into an anchor molecule for peptide synthesis. In another embodiment, a terminating group component can also be included in the anchor—in one embodiment, the terminating group component can include an aliphatic amine and/or alcohol and/or carboxylic acid capable of coupling to the end of an amino acid. In another embodiment, a linker component may also be included and provide a free moiety capable of participating in a reaction, such as a coupling reaction. Preferably, the bond formed by the free portion of the linker component may be labile to TFA-deprotection as known in the art, for example, as discussed herein.
It should be understood that the components described herein are described separately to better convey the different features that each component may contribute to a given anchoring molecule, and that the separate description of components herein should not be taken as limiting. It should be further understood that any of the components discussed herein may be considered protecting groups. For example, GAP components, AA (GAP) components, linker components, and terminator components may attach to a given molecule and protect the molecular region from undesired side reactions. The anchors discussed herein may further be considered protecting groups themselves. In another example, the anchors discussed herein can be attached to the C-terminus of an amino acid, such as via a nucleophilic moiety (e.g., NH, OH, etc.) that can attach a carbonyl carbon.
Claims (20)
1. A chemical composition comprising a GAP component, wherein the GAP component is selected from the group consisting of:
wherein:
R 4 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 5 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 6 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p1 -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30;
R 7 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30;
R 8 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30;
R 9 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p4 -wherein "p4" is an integer selected from the range of 0 up to 30 and including 30;
R 10 selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30;
"j" is an integer selected from the range of 0 up to 30 and including 30; and
"k" is an integer selected from the range of 0 up to 30 and including 30.
2. The chemical composition of claim 1, further comprising a linker component, wherein the linker component is selected from the group consisting of:
wherein:
y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O;
v is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a1 -wherein "a1" is an integer selected from the range of 0 up to 30 and including 30;
w is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a2 -, wherein "a2" is an integer selected from the range of 0 up to 30 and including 30;
x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30;
R 1 selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30;
R 2 selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and
"n" is an integer selected from the range of 0 up to 30 and including 30.
3. The chemical composition of claim 1, further comprising a terminator component, wherein the terminator component is selected from the group consisting of:
wherein:
R 4 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl Butyl and t-butyl;
R 5 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 6 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q1 -wherein "q1" is an integer selected from the range of 0 up to 30 and including 30;
R 7 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q2 -wherein "q2" is an integer selected from the range of 0 up to 30 and including 30;
R 8 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q3 -wherein "q3" is an integer selected from the range of 0 up to 30 and including 30;
R 9 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q4 -wherein "q4" is an integer selected from the range of 0 up to 30 and including 30;
R 11 selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh;
R 12 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30;
R 13 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and
R 14 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30.
4. The chemical composition of claim 1, further comprising a linker component, a terminator component, and a first amino acid component, wherein the GAP component is
Wherein:
R 4 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 5 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 6 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p1 -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30;
R 7 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30;
R 8 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30;
R 9 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p4 -wherein "p4" is an integer selected from the range of 0 up to 30 and including 30;
R 10 selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30;
"j" is an integer selected from the range of 0 up to 30 and including 30; and
"k" is an integer selected from the range of 0 up to 30 and including 30;
the linker component is
Wherein:
y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O;
w is-C (O) -;
x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30;
R 1 selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30;
R 2 Selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and
"n" is an integer selected from the range of 0 up to 30 and including 30;
the first amino acid component is
Wherein Z is 1 Selected from the group consisting of: s, O, NH, NMe, net, NBn, NPh, -C (O) -and- (CH) 2 ) d -, wherein "d" is an integer selected from the range of 0 up to 30 and including 30;
Z 2 selected from the group consisting of: s, O, NH, NMe, net, NBn, NPh, -C (O) -and- (CH) 2 ) e -, wherein "e" is selected from the range of 0 up to 30 andand includes an integer of 30;
"f" is an integer selected from the range of 0 up to 30 and including 30;
"g" is an integer selected from the range of 0 up to 30 and including 30;
R 3 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl, 2- (methylsulfanyl) ethyl,
Wherein "h" is an integer selected from the range of 0 up to 30 and including 30; and
the terminating group component is
Wherein:
R 11 selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh;
R 12 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30;
R 13 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and
R 14 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30.
5. The chemical composition of claim 4 comprising:
6. the chemical composition of claim 1, further comprising a linker component and a terminator component, wherein the GAP component is
Wherein:
R 6 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p1 -wherein "p1" is an integer selected from the range of 0 up to 30 and including 30;
R 7 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p2 -wherein "p2" is an integer selected from the range of 0 up to 30 and including 30;
R 8 Selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH) 2 ) p3 -wherein "p3" is an integer selected from the range of 0 up to 30 and including 30;
R 10 selected from the group consisting of: -C (O) - (CH) 2 ) m -and NH, wherein "m" is an integer selected from the range of 0 up to 30 and including 30;
"j" is an integer selected from the range of 0 up to 30 and including 30; and
"k" is an integer selected from the range of 0 up to 30 and including 30;
the linker component is
Wherein:
y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O;
w is-C (O) -;
x is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30;
R 1 selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30;
R 2 selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and
"n" is an integer selected from the range of 0 up to 30 and including 30; and
the terminating group component is
Wherein:
R 11 selected from the group consisting of: s, O, NH, NMe, net, NBn and NPh;
R 12 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q5 -H, wherein "q5" is an integer selected from the range of 0 up to 30 and including 30;
R 13 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q6 -H, wherein "q6" is an integer selected from the range of 0 up to 30 and including 30; and
R 14 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl, tert-butyl and- (CH) 2 ) q7 -H, wherein "q7" is an integer selected from the range of 0 up to 30 and including 30.
7. The chemical composition of claim 6 comprising:
8. the chemical composition of claim 1, further comprising a linker component and a terminator component, wherein the GAP component is
The linker component is
Wherein:
y is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh and O;
V is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a1 -wherein "a1" is an integer selected from the range of 0 up to 30 and including 30;
w is selected from the group consisting of: s, NH, NMe, NEt, NBn, NPh, O, -C (O) - (CH) 2 ) a2 -, wherein "a2" is an integer selected from the range of 0 up to 30 and including 30;
x is selected from the group consisting of: s, NH, NMe、NEt、NBn、NPh、O、-C(O)-、-(CH 2 ) a3 -, wherein "a3" is an integer selected from the range of 0 up to 30 and including 30;
R 1 selected from the group consisting of: - (CH) 2 ) b -H、-CCl 3 、-CF 3 Phenyl, isopropyl, tert-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl and dimethoxyphenyl, wherein "b" is an integer selected from the range of 0 up to 30 and including 30;
R 2 selected from the group consisting of: - (CH) 2 ) c -H, -CCl3, -CF3, phenyl, isopropyl, t-butyl, chlorophenyl, dichlorophenyl, methoxyphenyl, and dimethoxyphenyl, wherein "c" is an integer selected from the range of 0 up to 30 and including 30; and
"n" is an integer selected from the range of 0 up to 30 and including 30; and
the terminating group component is
Wherein:
R 4 selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 5 Selected from the group consisting of: H. methyl, ethyl, propyl, isopropyl, benzyl, isobutyl, sec-butyl and tert-butyl;
R 6 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q1 -wherein "q1" is an integer selected from the range of 0 up to 30 and including 30;
R 7 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q2 -wherein "q2" is an integer selected from the range of 0 up to 30 and including 30;
R 8 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q3 -wherein "q3" is an integer selected from the range of 0 up to 30 and including 30; and
R 9 selected from the group consisting of: -C (O) -, S, O, NH, NMe, net, NBn, NPh and- (CH 2) q4 -wherein "q4" is an integer selected from the range of 0 up to 30 and including 30.
9. The chemical composition of claim 8 comprising
10. A method of solution phase peptide synthesis, the method comprising the steps of:
attaching a first peptide to a first amino acid, wherein the first peptide is an anchor peptide;
coupling one or more additional amino acids to the first amino acid to form a second peptide; and
Removing the first peptide from the second peptide.
11. The method of claim 10, wherein the first peptide comprises a GAP component.
12. The method of claim 10, wherein the first peptide is formed by coupling a first protected amino acid to a second protected amino acid and attaching a linker to the first protected amino acid or the second protected amino acid, wherein the first protected amino acid is formed by attaching a first protecting group to a first side chain of a first amino acid component and the second protected amino acid is formed by coupling a second protecting group to a second side chain of a second amino acid component.
13. The method of claim 12, further comprising the step of:
coupling the first amino acid component with the second amino acid component;
attaching the linker to the terminus of the first amino acid component or second amino acid component;
attaching the linker to a third amino acid; and
coupling a fourth amino acid to the third amino acid.
14. A method of peptide synthesis comprising the steps of:
coupling an anchor to the first amino acid; and
Coupling a second amino acid to the first amino acid,
wherein the anchor comprises a compound selected from the group consisting of:
15. the method of claim 14, wherein the anchor is coupled to the C-terminus of the first amino acid.
16. The method of claim 14, wherein the anchor is coupled to a side chain of the first amino acid.
17. The method of claim 15, wherein the compound is
And wherein the anchor is coupled to the C-terminus of the first amino acid via a linker component.
18. The method of claim 17, wherein the anchor further comprises a terminating base component.
19. The method of claim 14, further comprising the step of removing the anchor from the first amino acid.
20. The method of claim 14, wherein the coupling of the second amino acid to the first amino acid occurs in 2-methyltetrahydrofuran.
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| Application Number | Priority Date | Filing Date | Title |
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| US202163201313P | 2021-04-23 | 2021-04-23 | |
| US63/201,313 | 2021-04-23 | ||
| PCT/US2022/071870 WO2022226536A1 (en) | 2021-04-23 | 2022-04-22 | Compositions for chemical synthesis of peptides |
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| EP (1) | EP4326735A1 (en) |
| JP (1) | JP2024515365A (en) |
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| US5516891A (en) | 1992-06-16 | 1996-05-14 | Kinerton, Ltd. | Liquid phase synthesis of peptides and peptide derivatives |
| IE20060841A1 (en) | 2006-11-21 | 2008-05-28 | Ipsen Mfg Ireland Ltd | Boc and fmoc solid phase peptide synthesis |
| CN108697770B (en) | 2015-12-21 | 2023-08-01 | 得克萨斯技术大学联合体 | System and method for solution phase GAP peptide synthesis |
| US20210079036A1 (en) * | 2018-05-31 | 2021-03-18 | Gap Peptides Llc | Compositions and methods for chemical synthesis |
| WO2019231760A1 (en) * | 2018-05-31 | 2019-12-05 | Gap Peptides Llc | Method for solution-phase peptide synthesis and protecting strategies therefore |
| EP3917937A4 (en) * | 2019-02-01 | 2022-11-23 | Sederma | Synthesis strategy for gap protecting group |
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| EP4326735A1 (en) | 2024-02-28 |
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